Vascular calcification is highly correlated with cardiovascular disease (CVD) mortality, especially in end stage renal disease (ESRD) and diabetic patients. In addition to the devastating effects of inappropriate biomineralization seen in cardiac valvulopathies, calciphylaxis and idiopathic infantile arterial calcification, vascular calcification is now recognized as a marker of atherosclerotic plaque burden as well as a major contributor to loss of arterial compliance and increased pulse pressure seen with age, diabetes and renal insufficiency. Whether or not vascular calcification can cause or exacerbate atherosclerosis is not known, and will be addressed in this proposal. Furthermore, arterial wall cells appear to play a particularly important role in mediating vascular calcification, especially in situations where osteochondral tissue is observed, such as in atherosclerosis and medial calcification associated with ESRD. This proposal seeks to identify the origins of the cells participating in osteochondral tissue formation, and mechanisms controlling their differentiation. These studies will aid in the development of novel therapeutic strategies to prevent and potentially reverse vascular calcification, an urgent need in the ESRD population.